Delayed release pharmaceutical formulation

ABSTRACT

The present invention relates to a delayed release pharmaceutical formulation for delivering an active agent to the intestine, a method of preparing such formulation and the use of such formulation in the treatment of gastrointestinal disorders.

PRIORITY

This application corresponds to the U.S. national phase of InternationalApplication No. PCT/EP2014/070128, filed Sep. 22, 2014, which, in turn,claims priority to European Patent Application No. 13.185334.3, filedSep. 20, 2013, the contents of which are incorporated by referenceherein in their entirety.

FIELD OF THE INVENTION

The present invention relates to a delayed release pharmaceuticalformulation for delivering an active agent to the intestine, a method ofpreparing such formulation and the use of such formulation in thetreatment of gastrointestinal disorders.

BACKGROUND OF THE INVENTION

The local treatment of bowel diseases, such as Crohn's disease andulcerative colitis, or the targeting of drugs to the intestine and inparticular to the colon for systemic administration is highlychallenging because conventional dosage forms rapidly release the drugin the upper gastrointestinal tract. Upon absorption into the bloodstream, the drug is distributed throughout the human body, resulting inpotentially severe side effects. In addition, the drug concentration atthe site of action, such as the inflamed colon, is low, leading to lowtherapeutic efficacies. To overcome these restrictions, drug releasefrom the dosage form should ideally be suppressed in the stomach andsmall intestine, but set on as soon as the target site is reached.

Different approaches have been described in the prior art to allow forsite-specific drugs delivery to the small and/or large intestine uponoral administration. Generally, a drug reservoir is surrounded by a filmcoating, which is poorly permeable to the drug in the uppergastrointestinal tract, but becomes permeable as soon as the target siteis reached. Furthermore, drug release might start right after oraladministration at a rate which is sufficiently small in order to assurethat drug is still present in the dosage form once the target site isreached.

Release of drugs in the colon typically requires a different approachthan the release in the small intestine. The colon is susceptible to anumber of disease states, including inflammatory diseases, irritablebowel syndrome, constipation, diarrhea, infection and carcinoma. In suchconditions, drug targeting to the colon would maximize the therapeuticeffectiveness of the treatment. The colon can also be utilized as aportal for the entry of drugs into the systemic circulation andtherefore can be effective in the treatment of diseases outside thecolon.

Various formulations have been developed for intestinal and inparticular colonic drug delivery, including pro-drugs as well asformulated dosage forms, with the latter being more popular since theconcept once proofed can be applied to other active agents. Examples fordevices and dosage forms for controlled release of an active agent tothe colon can be found in U.S. Pat. No. 4,627,851, WO 83/00435 and WO2007/122374.

Another problem is that colonic diseases are often associated with aninsufficient water-resorption and thus a significantly reduced residencetime of the drug at the site of action. In order to prevent immediatewash-out a fast release of the drug from the formulation immediatelyafter entering the colon is required. On the other hand, a fast releaseof the drug is associated with the risk of dose dumping in the uppergastrointestinal tract, for example if the delayed release coating isdamaged or for some other reason not sufficient for preventing prematuredrug release.

Furthermore, the site-specific release of an active agent to theintestine and in particular the colon is extremely sensitive tointer-individual variability. The release is dependent on the individualenvironment in the gastrointestinal tract, like pH or bacterial flora.This is even true for different stages of inflammation of the mucosa inthe small intestine due to individual pH shifts compared to non-inflamedmucosa. This problem occurs for example in ulcerative colitis atdifferent stages of inflammation or in Crohn's disease with differentsections of the small intestine affected. This makes it difficult totailor drug delivery in a way that the drug release takes place notearlier than for example in the terminal ileum.

Even though a variety of technical means to accomplish controlledrelease and especially site-specific release to the colon is known,there is an incessant need for further pharmaceutical formulations whichtailor the delivery of drugs and adapt it to new requirements.Especially for the treatment of inflammations of the mucosa of the smallintestine and in particular the colon further pharmaceuticalformulations are required which reliably prevent an early release of thedrug but at the same time provide release of the drug during its stay atthe site of action. Additionally, any excipients in such formulationsshould be low or not irritating in order to keep the mucosa protectedfrom further irritation.

SUMMARY OF THE INVENTION

Thus, the present invention relates to the problem of providing furthermeans for tailoring drug delivery to the intestine and in particular tothe colon. At the same time, the formulation should have low irritatingeffect on the mucosa. The release of the drug should start immediatelywhen the formulation has reached the intestine and preferably theterminal ileum so that the full dose of the formulation can be releasedduring the passage through the intestine and preferably the colon.

Precipitated calcium carbonate has been widely used as additives in thepaper and food industry and intensely evaluated as possiblepharmaceutical excipient. In 2000, a novel, highly porous structure ofcalcium carbonate, called functionalized calcium carbonate or modifiedcalcium carbonate, was described as a pigment filler or a mineral (WO00/39222). An improved process for preparing such functionalized(surface-reacted) calcium carbonate and the use of such functionalizedcalcium carbonate in paper, tissue paper, plastics, paints, or as acontrolled release or water treatment agent is disclosed in EP-A-2 264108.

T. Stirnimann et al. describe in Pharm Res, published online on Apr. 19,2013 the use of functionalized calcium carbonate as a pharmaceuticalexcipient for the preparation of orally dispersible tablets.

In WO 2010/037753 a carrier for the controlled release of active agents,comprising functionalized (surface-reacted) calcium carbonate isdisclosed. In the examples, natural oils such as amaranth, peppermintoil and limonene are used as active agents and the tablets prepared fromthe carrier containing the active agent are used as bath bombs, bathtablets, toothpastes and skin care formulations.

It has now surprisingly been found that porous particles, such asfunctionalized calcium carbonate, have excellent properties inpharmaceutical formulations for delivering an active agent to theintestine. Porous particles have the ability to adsorb and absorb a highamount of active agent resulting in a high drug load. Furthermore, itwas found that the drug is very quickly released from porous particles.Additionally, due to the small size of porous particles a high number ofsmall individual particles are released from a pharmaceuticalformulation containing these particles which can then spread over alarge area of the intestine for releasing the active agent.

The present invention therefore relates to a delayed releasepharmaceutical formulation for delivering an active agent to theintestine, comprising carrier particles and at least one active agentassociated with the carrier particles, wherein the carrier particles areporous and are surrounded by a material for intestinal targeting.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows dissolution profiles from FCC loaded with metronidazolebenzoate (MBZ), ibuprofen (IBU), losartan potassium (LK) and nifedipine(NP) in comparison to physical mixtures of drug and FCC with same drugcontent,

FIG. 2A shows an SEM picture of an unloaded FCC particle,

FIG. 2B shows an SEM picture of an FCC particle with a MBZ drug load of20%,

FIG. 2C shows an SEM picture of an FCC particle with a MBZ drug load of40%,

FIG. 2D shows an SEM picture of FCC particles with a MBZ drug load of50%,

FIG. 3 shows the dissolution profile of the FCC formulation with 40%drug load of MBZ obtained in example 2,

FIG. 4 shows the results of the stability tests conducted in example 2with FCC particles having a drug load of 20%,

FIG. 5 shows the results of the stability tests conducted in example 2with FCC particles having a drug load of 50%, and

FIG. 6 shows the difference in drug loading capacity between modifiedand unmodified FCC.

FIG. 7 schematically shows one example of a pharmaceutical formulationaccording to the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

A delayed release pharmaceutical formulation is understood as being aformulation which delays the release of the active agent from the timeof oral administration until the formulation reaches at least theintestine, preferably the terminal ileum, so that the active agent issubstantially released in the intestine and preferably the colon only.Once the formulation has reached at least the intestine and release ofthe active agent starts, the release may be immediate or slowly overtime.

As carrier particles any porous particles being pharmaceuticallyacceptable may be used. The carrier particles are preferably selectedsuch that they do not react with the active agent. For example, silicondioxide, magnesium aluminometasilicate, aluminosilicate, calciumsilicate, calcium carbonate, calcium phosphate, titanium dioxide,zirconium dioxide and other ceramics may be used as carrier particles.

The size of the carrier particles is not particularly limited and may beselected by the skilled person according to the requirements. Forexample, the carrier particles without active agent or any coatingmaterial can have a weight median grain diameter d₅₀ of from less than 1mm, more preferably of less than 0.1 mm and most preferably of less than0.05 mm, such as from 0.1 to 50 μm, more preferably from 0.5 to 25 μm,even more preferably from 0.8 to 20 μm, such as from 1 to 10 μm,measured according to the sedimentation method. Thus, the carrierparticles can for example be micro and nano particles.

The porosity of the carrier particles is related to their specificsurface area which preferably is in the range of from 5 m²/g to 200m²/g, more preferably from 20 m²/g to 80 m²/g and most preferably from30 m²/g to 60 m²/g, measured using nitrogen and the BET method accordingto ISO 9277.

In a preferred embodiment the carrier particles comprise calciumcarbonate, in particular precipitated or functionalized calciumcarbonate. Preferably, the carrier particles consist of functionalizedcalcium carbonate. The advantage of functionalized calcium carbonateparticles over other particles is that they are non-toxic and that theydegrade or dissolve fast, in particular at lower pH. Thus, they have noor only little irritating effect on the mucosa of the intestine, inparticular of the colon.

Functionalized calcium carbonate is known in the art. It is a highlyporous variation of precipitated calcium carbonate. As a result of itssmall pore size and enlarged surface area it is called “functionalizedcalcium carbonate” (FCC). Four different types of FCC (S01, S01, S03 andS04) with different particle size, pore size and pore structure arecurrently commercially available from Omya.

FCC can be prepared as described in WO 00/39222 and EP-A-2 264 108.Since it is prepared by reaction of the surface of natural or syntheticcalcium carbonate with carbon dioxide and an acid, FCC is also called“surface-reacted calcium carbonate”. Thus, FCC is obtainable by reactingnatural or synthetic calcium carbonate with carbon dioxide and one ormore acids, wherein the carbon dioxide is formed in situ by the acidtreatment and/or is supplied from an external source as described forexample in WO 2010/037753.

The natural calcium carbonate from which the FCC is prepared can beselected for example from the group comprising marble, calcite, chalcand dolomite, limestone and mixtures thereof. The synthetic calciumcarbonate from which the FCC may be prepared preferably is precipitatedcalcium carbonate including aragonitic, vateritic or calciticmineralogical crystal forms or mixtures thereof. The acids used in thepreparation of FCC can be selected from hydrochloric acid, sulfuricacid, sulfurous acid, hydrosulphate, phosphoric acid, oxalic acid andmixtures thereof.

The FCC preferably has a specific surface area of from 5 m²/g to 200m²/g, more preferably from 20 m²/g to 80 m²/g and most preferably from30 m²/g to 60 m²/g, measured using nitrogen and the BET method accordingto ISO9277.

The FCC preferably has a weight median grain diameter d₅₀ of from 0.1 to50 μm, more preferably from 0.5 to 25 μm, even more preferably from 0.8to 20 μm, particularly from 1 to 10 μm measured according to thesedimentation method.

The FCC preferably has an intra-particle porosity determined as the porevolume per unit particle volume within the range of from 20 vol.-% to 99vol.-%, more preferably from 30 vol.-% to 70 vol.-%, even morepreferable from 40 vol.-% to 60 vol.-%, such as about 50 vol.-%,calculated from a mercury porosimetry measurement.

The carrier particles, such as FCC, are capable of associating activeagents. The association can be an adsorption onto the surface of theparticles, be it the outer or the inner surface of the particles or anabsorption into the particles. Adsorption and absorption of the activeagent is essentially controlled by the pore size, which preferably is inthe range of from 10 to 100 nm, more preferably in the range of between20 and 80 nm, especially from 30 to 70 nm, such as about 50 nm.

Loading of the particles with the active agent can be conducted by anysuitable method known to a person skilled in the art, such as by soakingthe particles with a solution of the active agent in a suitable solvent,separating the soaked particles from the solution, for example byfiltration or centrifugation and drying the so obtained soakedparticles. However, it was found that loading the particles by thismethod results in low drug loads of only up to about 10% by weight basedon the total weight of the carrier particles including the weight of theactive agent. This has the disadvantage that high amounts (and volumes)of the final formulation must be administered in order to providesufficient active agent to a patient.

It has surprisingly been found that the drug load can considerably beincreased if the active agent is adsorbed/absorbed by the particlesusing an evaporation method. In this method, the unloaded particles aredispersed in a solution of the active agent in a suitable solventwherein the solution contains the desired total amount of active agentto be loaded onto and into the particles. The suspension is thenevaporated thereby allowing the active agent to deposit on and in theparticles. Using this method yields carrier particles being associatedwith at least 15% by weight, preferably at least 20% by weight, morepreferably at least 30% by weight, even more preferably at least 40% byweight, such as about 45% by weight of the at least one active agentbased on the total weight of the carrier particles including the weightof the at least one active agent.

Adsorption/absorption of the active agent on/in the porous particles byevaporation can be conducted using usual evaporation methods, such as byletting the solvent evaporate in an open vessel, for example at roomtemperature or increased temperature, at room pressure or in a closedvessel at decrease pressure. These methods, are, however, time consumingand on an industrial scale it can therefore be of advantage toadsorb/absorb the active agent on/in the porous particles using afluid-bed coating technique also known to the skilled person.Alternatively, the active agent may be adsorbed/absorbed by known spraydrying methods, for example by spray drying a solution of the activeagent together with suspended porous particles.

The active agent which may be used in association with the particles isnot particularly limited and can be selected by the skilled personaccording to the needs. For example, the active agent can be selectedfrom the group consisting of anti-inflammatory agents, anti-infectiveagents, immunomodulators and antibodies. The anti-inflammatory agent canfor example be a steroid, a corticosteroid, a non-steroidalanti-inflammatory agent or a herbal anti-inflammatory agent. Theanti-infective agent can for example be an antibiotic, a virustatic, anantimycotic, an anthelmintic or an agent against other micro-organisms(e.g. algae). Specific examples of suitable active agents are5-aminosalicylic acid, prednisolone, budesonide, fluticasone,azathioprine, cyclosporine, metronidazole and methotrexate. The activeagent can be present in its free base or acid form or as anypharmacologically acceptable derivative, such as ester, and/or saltthereof.

In the formulation of the present invention the carrier particles aresurrounded by a material for intestinal, preferably colon targeting. Itis understood that “surrounded” means that the carrier particles aresurrounded by the material for intestinal targeting such that thematerial substantially prevents and preferably completely preventsrelease of the active agent before the formulation reaches theintestine, preferably before it reaches the terminal ileum, mostpreferably before it enters the colon. This goal can be achieved bysurrounding the carrier particles by a coating of the material forintestinal targeting. The coating can be applied to each individualcarrier particle or to a core comprising a plurality of carrierparticles, such as a tablet core. In a further embodiment the coatingcan be applied to a capsule, such as a hard gelatin capsule, containingthe carrier particles. It is also envisaged that the carrier particlescan be combined into larger particles, such as granules, pellets orminitablets. These individual larger particles may then be coated withthe material for intestinal targeting and filled for example intosachets or capsules. Thus, “surrounded” does not mean that the carrierparticles are necessarily directly surrounded by the material forintestinal targeting but the material may be present in a shell orcoating being not in direct contact with the carrier particle.

In an alternative embodiment the carrier particles are within a matrixof the material for intestinal, preferably colon targeting. Non-coatedmultiparticlulate matrix systems for colon targeting are for exampledescribed by S. Krenzlin in Drug Development and Industrial Pharmacy,2011, 37(10):1150-1159.

The pharmaceutical formulation comprising the carrier particles beingsurrounded by a coating of the material of intestinal targeting maycomprise one or more further coatings being above or below for examplethe coating of the material for intestinal targeting or being betweenthe carrier particles and the matrix of the material for intestinaltargeting. It is also possible that the carrier particles are firstembedded within a matrix of the material for intestinal targeting andthe thus obtained larger particles are then coated with a furthercoating of the same or a different material for intestinal targeting.

Materials for intestinal targeting which can be used for surrounding thecarrier particles in the formulation of the present invention are wellknown to a person skilled in the art. Preferably, the material comprisesa compound which is insoluble in the gastrointestinal juice at a pH ofbelow 5 and which is soluble in the intestinal juice at a pH at or above5. Thus, this material dissolves in a pH dependent manner. The materialhas a pH threshold which is the pH below which it is insoluble and at orabove which it is soluble. The pH of the surrounding medium triggers thesolution of the material. Thus, none (or essentially none) of thematerial dissolves below the pH threshold. Once the pH of thesurrounding medium reaches (or exceeds) the pH threshold, the materialbecomes soluble.

By “insoluble” it is understood that 1 g of the material requires morethan 10,000 ml of solvent (surrounding medium) to dissolve at a givenpH. By “soluble”, it is understood that 1 g of the material requiresless than 10,000 ml, preferably less than 5,000 ml, more preferably lessthan 1,000 ml, even more preferably less than 100 ml or 10 ml of solventto dissolve at a given pH. “Surrounding medium” means the medium in thegastrointestinal tract, such as the gastric juice or intestinal juice.Alternatively, the surrounding medium may be an in vitro equivalent ofthe medium in the gastrointestinal tract.

The normal pH of gastric juice is usually in the range of 1 to 3. Thematerial for intestinal, preferably colon targeting is insoluble belowpH 5 and soluble at or above pH 5. The material therefore is usuallyinsoluble in gastric juice. Such material may be referred to as an“enteric” material. The pH of intestinal juice gradually increases toabout 7 to 8 along the small intestine. The material for intestinaltargeting therefore becomes soluble in the terminal ileum/colon andallows release of the active agent from the carrier particles. Thematerial preferably has a pH threshold of 6.5, more preferably of 7.

Examples of suitable materials for intestinal targeting and inparticular for the preparation of a coating surrounding the carrierparticles are acrylate polymers, cellulose polymers and polyvinyl-basedpolymers, chitosan, its derivatives or other polymers. Examples ofsuitable cellulose polymers include cellulose acetate phthalate,cellulose acetate trimellitate and hydroxypropylmethyl cellulose acetatesuccinate. Examples of suitable polyvinyl-based polymers includepolyvinylacetate phthalate.

In one embodiment the material for intestinal targeting can be aco-polymer of a (meth)acrylic acid and a (meth)acrylic acid C₁₋₄ alkylester, for instance, a copolymer of methacrylic acid and methacrylicacid methyl ester. Suitable examples of such copolymers are usuallyanionic and not sustained release polymethacrylates. The ratio ofcarboxylic acid groups to methylester groups in these co-polymersdetermines the pH at which the copolymer is soluble. The acid:esterratio may be from about 2:1 to about 1:3, e.g. about 1:1 or, about 1:2.The molecular weight of such anionic copolymers is usually from about120,000 to 150,000, preferably about 135,000.

Known anionic poly(methycrylic acid/methyl methacrylate) co-polymersinclude Eudragit® L (pH threshold about 6.0), Eudragit® S (pH thresholdabout 7) and Eudragit® FS (pH threshold about 7). Eudragit® L 100-55which is a copolymer of methacrylic acid and ethylacetate and which hasa pH threshold of about 5.5 is also suitable. The Eudragit® copolymerscan be obtained from Evonik.

Mixtures of two or more materials for intestinal targeting may be usedas appropriate.

Optionally, conventional excipients such as plasticizers for filmformation (for example triethylcitrate) and anti-tacking agents (such asglyceryl monostearate) may be included in amounts up to 30% by weight ofthe total weight of the coating preparation.

The thickness of the coating surrounding the carrier particles istypically from about 10 μm to about 150 μm. The thickness of a specificcoating will, however, depend on the composition of the coating andsurface area of the carrier.

In addition or alternatively to the above described compounds having apH threshold the material for intestinal, preferably colon targeting maycomprise a compound which is susceptible to attack by colonic bacteria,such as polysaccharides. Suitable polysaccharides are for examplestarch, amylose, amylopectine, chitosan, chondroitine sulfate,cyclodextrine, dextrane, pullulan, carrageenan, scleroglucan, chitin,curdulan and levan.

Furthermore, nutriose® is suitable as material for colon targeting, inparticular for forming a matrix surrounding the carrier particles.Nutriose® is a water-soluble, branched dextrin with high fiber contentsobtained from wheat starch which is commercially available from RoquetteFreres. This compound may be used in combination with for examplemicrocrystalline cellulose, polyvinylpyrolidone or lipids, such ashardened soy bean oil, glyceryl tristearate, sasol wax, microwax HG,microwax HW, or the like.

The pharmaceutical formulation of the present invention may containfurther pharmacologically acceptable excipients known to a personskilled in the art. For example, the carrier particles can be directlycompressed into tablet cores either alone or in combination with usualfillers, lubricants, etc. and the tablet core can then be surrounded bythe material for intestinal targeting. In another embodiment the carrierparticles can be granulated into granules either alone or in combinationwith usual excipients, such as fillers or granulation aids before theyare either compressed into tablet cores or directly surrounded by thematerial for intestinal targeting.

The final pharmaceutical formulation is an oral dosage form intended fororal administration and being in the form of for example tablets,granules, mini-tablets, pellets or capsules.

The pharmaceutical formulation of the present invention has theadvantage that the carrier particles generally have a small particlesize. Therefore, the pharmaceutical formulation contains a high numberof individual carrier particles which may separate from each other whenthe formulation disintegrates upon dissolution of the material forintestine targeting. Thus, a high number of carrier particles arereleased and can spread over a large area of the intestine therebyresulting in a uniform release of the active agent within the intestine.

Furthermore, the release of the active agent from the carrier particlesdepends on the size of the carrier particles and the size of their poresas well as of the physical and chemical properties of the active agentitself. Thus, in some cases, the active agent is immediately releasedfrom the carrier particles while in other cases the active agent may bereleased over a prolonged time period. It would therefore be desirableto provide means for tailoring the release profile of a given activeagent according to the specific needs of the patient or the disease tobe treated.

Furthermore, it was found that for example lipophilic active agents tendto be difficult to be loaded onto and into the carrier particles. Itwould therefore be desirable to provide carrier particles allowing ahigher drug load in particular for lipophilic active agents.

It was surprisingly found that both problems can be solved by coatingthe carrier particles at least partially with a compound which impartshydrophobicity or hydrophilicity to the surface of the carrierparticles. This can be accomplished for example by reacting the carrierparticles and in particular the functionalized calcium carbonate with ahydrophobic or hydrophilic compound, such as a fatty acid, for example astearic acid. It has been found that such compounds react with thesurface of the functionalized calcium carbonate thereby forming a filmor coating of for example stearate molecules. These molecules impart forexample hydrophobicity to the surface of the carrier particles andthereby allow for a higher load of a hydrophobic drug. Furthermore, iffor example a hydrophobic drug is loaded onto and into a hydrophobicallymodified carrier particles, the release of the active agent is retardedand the active agent will be available in the intestine over a prolongedtime period.

In a further embodiment the carrier particles in the pharmaceuticalformulation of the present invention are at least partially coated witha mucoadhesive compound.

Coating the particles with a mucoadhesive compound has the advantagethat the carrier particles are retained in the intestine for a prolongedtime so that the active agent may be released also for a prolonged timewithout the risk that the carrier particles leave the intestine beforethe active agent has been sufficiently released. The retention of theparticles at the mucosal surface can contribute to extended residencetime in the target region.

Suitable mucoadhesive compounds are known to a person skilled in theart. Examples for synthetic mucoadhesive polymers are the variousacrylic acid derivatives, in particular polyacrylates (also known ascarbomers which are commercially available as Carbopols®),polyvinylpyrrolidone (PVP), and polyvinylalcohol. Alginate, pectin andguar gum can be mentioned for natural mucoadhesive polymers. Chitosanand many cellulose derivatives are known as semi-synthetic mucoadhesivepolymers.

An example for a pharmaceutical formulation according to the inventionis schematically shown in FIG. 7. This figure shows active agentassociated with carrier particles which are coated with a mucoadhesivecompound. The such coated particles are contained within a capsule whichis surrounded by a coating for intestinal targeting.

In a further embodiment the carrier particles in the pharmaceuticalformulation of the present invention are at least partially coated witha sustained release coating. The sustained release coating may bepresent instead of the mucoadhesive compound or in combination with themucoadhesive compound. Preferably, the carrier particles are at leastpartially coated with both, a mucoadhesive compound and a sustainedrelease coating because in this case, the carrier particles are retainedin the intestine for a prolonged time and simultaneously the activeagent is released over a prolonged time.

Suitable compounds for preparing the sustained release coating are knownto the skilled person. For example, Eudragit RS, Eudragit RL, EudragitNM, Eudragit NE, ethyl cellulose, Compritol ATO 888, Precirol ATO 5,Geleol Mono and Diglycerides NF may be used.

The sustained release coating may be applied onto the porous particlessimultaneously with the mucoadhesive compound or before or after themucoadhesive compound. Preferably, the particles are first at leastpartially coated with the sustained release coating and afterwards themucoadhesive compound is applied to the such coated particles.

The present invention furthermore provides a method of preparing theabove described delayed release pharmaceutical formulation. This methodcomprises the steps of loading porous carrier particles, such asfunctionalized calcium carbonate, with at least one active agent toobtain loaded carrier particles and surrounding the loaded carrierparticles with a material for intestinal, preferably colon targeting.

Loading the carrier particles with the active agent can be conducted byconventional methods as described above. In one embodiment loading isconducted by suspending the carrier particles in a solution of theactive agent in a suitable solvent, such as an alcohol, in particularethanol or methanol, any other organic solvent, such as acetone, orwater. The solvent is then removed from the suspension by evaporation,preferably under reduced pressure. Alternatively, the carrier particlescan be loaded with the active agent by a fluid-bed coating technique orby spray drying.

Surrounding the loaded carrier particles with the material forintestinal targeting can be conducted by usual methods, such as spraycoating for obtaining a coating, or extrusion methods, such as meltextrusion, for obtaining a matrix.

The method may comprise other steps such as granulation and/orcompression steps of the loaded carrier particles alone or incombination with one or more excipients.

Furthermore, the present invention relates to the above describeddelayed release pharmaceutical formulation for use in a method oftreatment of gastrointestinal disorders, such as inflammatory disordersof the gastrointestinal tract including Crohn's disease and ulcerativecolitis, inflammatory bowel disease, constipation, diarrhea, infection,and carcinoma, particularly colon or colorectal cancer.

The invention will now be further explained by the following exampleswhich are not intended to be construed as limiting.

EXAMPLE 1

Drug-loaded FCC (dl-FCC) was produced with metronidazole benzoate (MBZ),ibuprofen (IBU), losartan potassium (LK) and nifedipine (NP) indifferent drug to drug-carrier ratios. The series of different drugloads (DL) included 25, 30, 35, 40, 45 and 50% (w/w).

The weighted drug was put in a round bottom flask and dissolved in 50 mlof the organic solvent. Acetone served as drug loading solvent for IBU,MBZ and NP, whereas LK was dissolved in methanol. Bulk FCC (5.0 g) wasadded and sonicated (Retsch, Switzerland) for 5 min to disperse theparticles and degas the solvent. The solvent was evaporated in a rotaryevaporator (Buchi RE 121 or R-114) with a waterbath set to 40° C. (Buchi461 or B-480). Pressure was stepwise decreased by 100 mbar per 0.5 hdown to 20 mbar, and held for at least 1 hour. Initial pressure settingwas 300 mbar for methanol and 480 mbar for acetone. After removal of theresidual solid from the round bottom flask, the product was gentlymilled with mortar and pestle, and subsequently sieved through 250 μmand 90 μm mesh screens (Retsch, Switzerland). The dl-FCC was vacuumdried for 24 h at room temperature (KVTS 11, Salvis AG, Switzerland)under constant nitrogen injection.

Drug release of IBU, LK, MBZ and NP was studied with a USP2 dissolutionapparatus (SOTAX, Switzerland). Dissolution buffer (pH 6.8, 0.05 M)consisting of sodium phosphate was produced according to the standardsof the international Pharmacopoeia. Addition of sodium lauryl sulphate(SLS) was necessary to reduce surface tension of the medium and toassure sinking of the drug-loaded and drug-mixed formulations. Thedissolution medium was continuously transferred to theUV-spectrophotometer (Amersham Bioscience, Ultrospec 3100 pro) andreturned back to the dissolution vessels with a peristaltic pump (IPC,Ismatec, Switzerland). Absorbance was measured every minute at thewavelengths described in the HPLC-UV methods. Samples were measured induplicates (NP) or triplicates and sink conditions were provided in allexperiments. Path length of the cells was adjusted (0.2 or 1.0 cm) toobtain absorbances in the linear and valid range of the calibrationstandard.

FIG. 1 shows dissolution plots of drug-loaded FCC in comparison tophysical mixtures of drug and FCC (dm-FCC). Immediate and complete drugrelease within the first minute was observed for LK- and IBU-loaded FCCand corresponding reference formulations (dm-FCC). In contrast, MBZ- andNP-loaded FCC showed faster drug dissolution in comparison to thedrug-mixed FCC. After 3 min, 80% was released from MBZ-loaded FCC,whereas 6 min passed until 80% of the MBZ-mixed formulation weredissolved. NP-loaded FCC was releasing the first 80% 2.5-fold fasterthan the NP-mixed FCC. In summary, the investigated drug-loaded FCCformulations provided immediate drug release and showed no reduction indissolution rate, but faster release for NP- and MBZ-loaded FCC.

EXAMPLE 2

2.1 Drug Loading

Drug loading was performed with 5 or 5.5 g of FCC S01 and varyingamounts of MBZ. Acetone was used to dissolve MBZ and disperse FCC. Thesolvent was removed and MBZ re-crystallized on the surface of FCC. Thesolvent evaporation method allowed controlling the resulting massfraction of the drug. Drug-load levels of 20%, 30%, 35%, 40%, 45% and50% (w/w) were produced.

The weighted MBZ was put in a round bottom flask and dissolved in 50 mlacetone. The required amount of FCC was added and sonicated for 5 min todisperse the FCC and degas the solvent. Acetone was evaporated at 40° C.and 480 mbar using a rotary evaporator (Buchi RE 121 or R-114) and awater bath (Büchi 461 or B-480). The pressure was stepwise decreased to400, 300, 100, and 5 mbar in intervals of 0.5 h. The average speed ofpressure drop was approximately 200 mbar/h. The residual solid wasremoved from the round bottom flask, transferred into a petri dish andvacuum dried overnight at room temperature.

2.2 SEM Characterization

A differentiated characterization of FCC particles by Scanning ElectronMicroscopy (SEM) was conducted to evaluate the morphological differenceafter the drug-loading procedure. An unloaded FCC particle is shown inFIG. 2A. The outer surface of FCC is built up by interconnected panels,which is a main morphological characteristic of FCC. FIG. 2A shows atypical picture of the distinctive pore structure.

SEM analysis of FCC particles with a MBZ drug load of 20% showedindividual particles without agglomerates. FCC particles with notablepore filling were sparsely found. Most of the investigated particlesshowed no visible difference compared to unloaded FCC. A typical exampleis shown in FIG. 2B, where pore size and pore structure remainedunchanged. These observations let assume that more drug could be loaded.

Two batches of 40% DL were investigated and showed good reproducibility.No MBZ crystals (>2 μm) were observed and both batches revealed the sameprevalence and size-range of agglomerates. All particles showed only afew free pores what indicated a reaching of the capacity limits for drugloading. FIG. 2C is a typical example of single FCC particles with acomplete drug load. The upper edges of the characteristic FCC panelswere stretching out of the surface, indicating that the pores werefilled with the drug; and not just covered. Compared to unloaded FCCparticles the surfaces were considerably smoother, but still exhibited arough morphology.

A drug load of 50% resulted in the formation of many agglomerates andbig separate MBZ crystals (FIG. 2D). This observation demonstrated thelimit of drug-load capacity of FCC in this particular example at 40-45%.

2.3 Dissolution

A mixture of 96% drug-loaded FCC (MBZ DL 40%) and 4% Ac-Di-Sol wasproduced and tablets of 500 mg (round shape, d=8 mm) were compacted with10 kN (Styl'One, Medelpharm). Drug release of MBZ out of FCC was studiedwith a USP2 dissolution apparatus (SOTAX). The tablets were cut in halfto achieve sink conditions in 1 l of de-ionized water. Average mass ofMBZ was 97.7 mg per halved tablet. Samples were taken from thedissolution vessels every minute by a custom-built auto-sampler andabsorbance was measured spectrophotometrically at 320 nm (AmershamBioscience, Ultrospec 3100 pro). The peristaltic pump (Ismatec IPC) andthe UV-spectrophotometer were controlled by a computer software.

Tablets were prepared to yield a hardness of 110 N. To measure the drugrelease from individual FCC particles, Ac-Di-Sol was used assuperdisintegrant. The disintegration of the tablet into singleparticles happened within the first minute and the distribution of thedrug-loaded sub-units simulated the desired performance in the colon.FIG. 3 shows the dissolution profile of the FCC formulation with 40%drug load of MBZ. A complete release of MBZ happened within 30 min.

2.4 Stability Testing

The compatibility of MBZ and FCC was investigated by an acceleratedstability study. Drug loaded FCC particles with 20 and 50% drug contentwere stored at 25° C., 40° C. and 60° C. over a period of 25 days. Onseveral days the MBZ content was analyzed by HPLC-UV.

Only the active substance (MBZ) was detected but not any degradationproducts from hydrolysis such as metronidazole (MTZ) or benzoic acid.

FIG. 4 shows the remaining MBZ content in % of the total powder mass.The results from HPLC-UV quantification showed deviation during theevaluation period, but were close to the theoretical drug load of 20%.The same pattern could be observed for FCC with a theoretical drug loadof 50% (FIG. 5). MBZ content was fluctuating during the stabilitytesting, but the average drug content remained almost constant.

EXAMPLE 3

3.1 Surface Modification

Method M1: Stearinisation in Aqueous Solution

5 g FCC S03 was mixed in a round-bottom flask with 100 ml degassedwater. This slurry was heated up to 100° C. In a second round-bottomflask 1 g stearic acid (e.g. 200 mg stearic acid per gram FCC) and 20 mlwater were heated to 100° C. Two drops of 1 molar NaOH were added toimprove the solvation. The solution was then added to the first flask.This mixture was kept at given temperature for one hour. In order toprevent evaporation of the solvent a reflux condenser was applied. After15 minutes, a massive amount of foam was formed, filling the flask. Asit evidently prevented the FCC in the foam from further reacting withthe solution, the flask was removed from the reflux condenser andswiveled thorough until the foam collapsed. This procedure was repeatedevery 15 minutes.

After an hour, the liquid was carefully poured off. The foam, that didnot show any signs of wetness, was dried at 100° C. overnight to removepossibly trapped solvent from the pores.

Method M2: Stearinisation in 50% Ethanol-Water (FCC 200-Mod)

The solvent was changed to a mixture of 50% ethanol and 50% degassedwater. The procedure was the same as in case of aqueous solution (M1).The reaction temperature was 83° C. conditioned by the temperatureplateau of the solvent mixture.

3.2 Drug Loading

In this method, carbamazepine was dissolved in 50 ml ethanol and 0.5 gof FCC 200Mod was added. The mixture was then stirred for twentyminutes. Afterwards the loaded particles were separated from the solventwith a Büchner funnel and dried overnight in the vacuum drier at 40° C.

The difference in drug loading capacity between modified and unmodifiedFCC is shown in FIG. 6. The ratio of drug load in unmodified FCC and200-Mod is 1:3 at 20 mg/ml.

1. A delayed release pharmaceutical formulation for delivering an activeagent to the intestine, comprising carrier particles and at least oneactive agent associated with the carrier particles, wherein the carrierparticles are porous particles and are surrounded by a material forintestinal targeting.
 2. The delayed release pharmaceutical formulationaccording to claim 1, wherein the carrier particles comprisefunctionalized calcium carbonate.
 3. The delayed release pharmaceuticalformulation according to claim 2, wherein the functionalized calciumcarbonate is a surface reacted calcium carbonate which is obtainable byreacting natural or synthetic calcium carbonate with carbon dioxide andone or more acids, wherein the carbon dioxide is formed in situ by theacid treatment and/or is supplied form an external source.
 4. Thedelayed release pharmaceutical formulation according to any of thepreceding claims, wherein the at least one active agent is adsorbed ontoand/or absorbed into the carrier particles.
 5. The delayed releasepharmaceutical formulation according to any of the preceding claims,wherein the carrier particles are associated with at least 15% byweight, preferably at least 20% by weight of the at least one activeagent based on the total weight of the carrier particles including theweight of the at least one active agent.
 6. The delayed releasepharmaceutical formulation according to any of the preceding claims,wherein the active agent is selected from the group consisting ofanti-inflammatory agents, anti-infective agents, immunomodulators andantibodies.
 7. The delayed release pharmaceutical formulation accordingto claim 6, wherein the anti-inflammatory agent is a steroid, acorticosteroid, a non-steroidal anti-inflammatory agent or a herbalanti-inflammatory agent, and wherein the anti-infective agent is anantibiotic, a virustatic, an antimycotic, an anthelmintic or an agentagainst other micro-organisms.
 8. The delayed release pharmaceuticalformulation according any of the preceding claims, wherein the carrierparticles are surrounded by a coating of the material for intestinaltargeting.
 9. The delayed release pharmaceutical formulation accordingto any of the preceding claims, wherein the carrier particles are withina matrix of the material for intestinal targeting.
 10. The delayedrelease pharmaceutical formulation according to any of the precedingclaims, wherein the material for intestinal targeting comprises acompound which is insoluble in the intestinal juice at a pH below 5 andwhich is soluble in the intestinal juice at a pH at or above
 5. 11. Thedelayed release pharmaceutical formulation according to any of thepreceding claims, wherein the material for intestinal targeting is amaterial for colon targeting.
 12. The delayed release pharmaceuticalformulation according to claim 11, wherein the material for colontargeting comprises a compound which is susceptible to attack by colonicbacteria.
 13. The delayed release pharmaceutical formulation accordingto any of the preceding claims wherein the carrier particles are atleast partially coated with a compound which imparts hydrophobicity orhydrophilicity to the surface of the carrier particles.
 14. The delayedrelease pharmaceutical formulation according to any of the precedingclaims, wherein the carrier particles are at least partially coated witha mucoadhesive compound and/or sustained release coating.
 15. A methodof preparing a delayed release pharmaceutical formulation as defined inany of claims 1-14, comprising the steps of loading porous carrierparticles with at least one active agent to obtain loaded carrierparticles and surrounding the loaded carrier particles with a materialfor intestinal targeting.
 16. A delayed release pharmaceuticalformulation as defined in any of claims 1-14 for use in a method oftreatment of gastrointestinal disorders.